Polynuclear cyclic oxyketones and derivatives thereof and process of making same



Patented Jan. 10, 1939 UNITED STATES PATENT OFFICE POLYNUCLEAR CYCLIC OXYKETONES AND DERIVATIVES THEREOF AND PROCESS OF MAKING SAME Leopold mam, Zurich, and Albert Wettstcin,

Basel,

Switzerland No Drawing.

August 16, 1937, land Allllllt 2, 1985 Serial Switzerland, assignors to the iirm Society of Chemical Industry in Basic.

Basel,

Original application June 15, 1838, Serial No. 85,437. Divided and this ap N0. 159,435. In Swimpiioation 3 Claims. (01. 260-397) changed, are not yet known.

This invention is based on the observation that such new oxyketones and their esters are obtainable by partially saponiiying a diester 01' a die] of the type of the saturated or unsaturated androstane-diols- (3, 17),

oxidizing the free carbinol-group (in 3- 3 position) thus produced (it necessary with temporary protection of the double bonds present) to a keto-group and, if,desired, purifying and saponiiying the keto-ester thus obtained. a

A particularly advantageous procedure consists in starting from a mixed di-ester of a diol oi the type of the saturated or unsaturated androstane-diols, particularly those esters in which the hydroxyl group in 3-position is esterifled with an acid radical which is comparatively easily saponiflable, whilst that in 17-position is esterifled by an acid radical which is saponiflable with comparative diillculty. One can also start from afree diol, partially esteriiy this and oxidize the resulting diol, mono-esteriiied in 17-position, in the manner described above. advantageously after purification.

The same oxyketone can be produced by subjecting the tree diol, ii desired with ternporary protection or double bonds present, directly to a partial oxidation and separating from the reaction product the compound which has undergone oxidation at the 3- position. Y

Finally, it is also possible to obtain these new oxyketones by subjecting to a partial reduction a diketone of the type of the androstane-dione-(3, 17) and separating from the reduction product the 3-keto-1'7- H oxy-compound.

The carbinol-group in 3-position can also Partial saponiilcation 1 Partial oxidation or dehydrogenation be oxidized to a keto-group by the action oi a dehydrcgenating agent;

The various methods may be illustrated by the following formulae, in which Am and Ac: mean the same or diflerent acyl radicals and R represents hydrogen or a monovalent hydrocarbon radical:-

Partial csterlflcation 0 Hi cm R on on. R

Oxidation or --y dehydrogenation HI. Esteriiicstion IV.

( Saponiiication OH: R 0

Partial reduction CHI H.

H. R CH. OH: R jo-Aa' Jon i no A As suitable oxidizing agents for converting III into IV or for converting V into VII there may be used, for example, a hexavalent chromium compound such as chromic acid in glacial acetic acid; furthermore copper oxide and .the like. In

' the oxidation of an unsaturated diol or its ester conversion of the free diols into 3-keto-17-oxy-' compounds by oxidation of the 3=carbinol-grcup proceeds in a particularly advantageous manner in cases in which the nuclear carbon atom in l'l-position is linked to .a hydrocarbon radical.

When a-mixed di-ester is to be subjected to par-- tlal saponification there are advantageously used those which contain in 3-position the radical of a lowerfatty acid such as acetic acid or formic acid, and in 17-position the radical of a higher fatty acid such as a valeric acid, or a carbamic acid, benzoic acid, a toluic acid, hexahydrobenzoic acid or a hydrohalogen acid.

The aforesaid inixed di-esters are obtained by causing to act on a 3-mono-ester of a diol of the type of the saturated -or unsaturated androstane diols an acylating agentcontaining an acid radical different from that. already present in the molecule of the mono-ester. i I The partial saponification maybe conducted, for example, in methyl alcohol, ethyl alcohol or in a higher alcohol, in dioxane, acetone or the like. If an alcoholis used re-esteriflcation generally occurs in addition tothe actual saponiflcation, so that the quantity of alkali solution consumed is frequently considerably less than the calculated quantity. One is therefore not restricted tothe-use of the calculated quantity of alkali, but may use a larger or a smaller quantity. By this nieans, as well as by the concentration of the alkali-solution and the tempera-- ture, the duration of the reaction may be favorably influenced. v

Suitable acylating agents for converting II into 111 and for converting VII into IV are, for instance, acids, acid halides and acid anhydrides,

-for example benzoic acid, acetic acid, formic acid, benzoyl chloride, acetyl chloride, acetic anhydride and the like, if required in the presence of an acid binding agent such as a tertiary base or an alkali.' Particularly when an acid halide or an acid anhydride is used there is advantageously. taken for the partial esteriflcation of II only a quantity of acylating agent sumcient for esterifying one hydroxyl-group.

In the partial reduction of VI the hydrogenation is interrupted when there has been absorbed a quantity of hydrogen sufflclng for the reduction of one carbonyl-group.

For the dehydrogenation of the carbinol-group to the keto-group there may be used with advanta'ge any of the usual dehydrogenating agents, for instance selenium, sulfur, or a metallic catalyst belonging to the group of hydrogenating or de-,-

hydrogenating catalysts such as copper, platinum, palladium, gold, nickel and the like, if de- 'siredin the presence of a hydrogen acceptor such'as naphthalene, phenol, cynnamic acid, fur maric acid or the like.

of 90 per cent. strength.

It is easily possible to isolate in a pure form the oxyketone produced either by direct crystallization or by preparing a suitable derivative. Such derivatives are obtained,- for example, by reaction with the usual ketone reagents such as semi-ca'rbazide, thiosemicarbazide, hydro'xylamine, aminoguanidine, phenylhydrazine and its substitution products, neutral or basic acylhydrazides. For purification and separation acylation is often useful, for example by means of acetic anhydride, benzoyl chloride, dinitrobenzoyl chloride or the. like. By the action of hydrolytically acting agents the above compounds can be split into their components. For separating the 3-keto-compound from any 3-oxy-compound-which may have been formed as a by-- product there have been proved advantageous also the saponines such as digitonine especially when the steric arrangement of the hydroxylgroup in 3-position corresponds with that of cholesterol.

.Among the diols of the type of the saturated or unsaturated androstane-diols-(3, 17) there are to be understood not only the stereo-isomeric androstane-diols in question themselves, but also their nuclear substitution products, for example the compounds substituted in 17-positlon by a hydrocarbon radical such as an alkyl-, aralkylor aryl-group; so also the scope of the 3, l'l-androstane-diones extends also to the isomeric 8, 1'7- aetiocholanediones. Theifollowing diols,'for example, are suitable parent materials for the invention: the androstane-diols-(S, 17), the A or ,A -androstene-diols-(ii, 1'1), the Ti -methylor 17-ethyl-androstane-diols-3, 17-), the 1"!- methylor 17-ethyl-androstene-diols-(3, 1'1),-in which in each case the carbinol-groups in both 3- and l'l-positions may be in cis-, or epi-, or in trans-position. Suitable parent materials of the Y dione-series are among others the androstanedione-(3, 17), the.At -androstene dione-(ii, 17) and the aetiocholane-dione-(3, 17)

The new ox'y-ketones as well as their esters have powerful efiects on the combs of capons and also on the seminal vesicle.

The following examples illustrate the inven-.

tion

Example 1 3.76 grams of androstane-diol-(3,17)-diacetate of the formula CH cm H 8 fi-j-OQQCH:

cn coo of melting point 127-i28 C. are allowed to stand for 48 hours at room temperature in 1000 cc. of 11/ 100-methyl-alcoholic potash solution. After concentrating the solution, the ll-acetoxy-androstane-ol-(3), produced by the partial saponiflcation. is precipitated by addition of water, ill-,-

tered, washed with waterand dried in a vacuum over phosphorus pentoxide. It may be used without further purification for making androstane- 'ol-(1.7)-one-(3). For this purpose the product is dissolved in 50 cc. of glacial acetic acid and thereis added, while cooling, 8. solution of 0.8 gram of chromium trioxide in 25 cc. of acetic acid After standing for 14 hours at room temperature some methanol is added for thepurpose of reducing the small exslum hydroxide. After neutralizing, the solution v i the which has been produced by partial saponiflcacess of chromic acid. The solution is diluted with water and the precipitate formed dissolved in ether. The ethereal solution is washed with dilute sodium carbonate solution and water and evaporated. From the residue the acetate or androstane-ol-(l'l) -one-(3) or melting point 1585-1595 C. is isolated, preferably by means of the sparingly soluble semicarbazone, which may OH: H

By recrystallization from hexane or dilute alcohol the latter may be purified. It iorms' colorless Example 2 CHa crncoo oi. melting point 165-166" at. whichithe we hydroxyl groups are probably inwtrana -contlgiiration, are allowed to stand at room temperature for 40 hours in 1000 cc. of methyl alcohol towhichhave been added previously 0.45 gram oi potasis strongly concentrated in a vacuum and then crude A -l'l-acetoxy-androstene-ol-(3) tion, is precipitated by addition of water, extracted with ether and obtained by evaporation of the ether. The crude mono-ester thus obtained is purified by recrystallization from hexane, with removal of sparingly soluble constituents and the purified ester of melting point 146-l4 8 C. is taken up in 50 cc. of glacial acetic acidand, while cooling, there is added, drop by drop, a solution of bromine in glacial acetic acid as long as there is immediate decolorization. Finally, also in the cold, there is added 1 gram of cromium trioxlde dissolved in 30 cc. of acetic acid of 90 per cent. strength and the whole is allowed to stand over-night at room temperature. The whole lsthen poured into 1 liter of water, the

precipitated product is filtered and washed with much water. The brominated-ketone thus obtained is dissolved for the purpose oi debrominating it in 50 cc. of glacial acetic acid, and after addition of 20 grams of zinc dust the whole is heated while vigorously shaking for 12 minutes on the boiling water-bath. There follow filtration through a glass filter, washing with a little hot glacial acetic acid, precipitating the solution with water and extraction with ether. The

ethereal solution is washed with dilute sodium carbonate solution and water and then evaporated to yield a residue, from which A-androstene- 01-(17) -one-(3) -acetate may be isolated by means of its semicarbazone, and after recrystallization from hexane melts at 141 C. By saponi iication it may be converted into the free oxyketone, namely M -androstene-ol-(l'l) -one-(3) of the formula CH CH: H

which melts at 155 C. When using other esters, there are obtained the corresponding keto-esters in an analogous manner, for instance A -androsteneol-(l'l)-one-(3)--benzoate of melting point 194-195" C. v l

The-.propionate of melting point 121-l23 The n-butyrate of melting point 111-113 The 'iso-butyrate'of melting point 131-133 The n-valerianate of melting point 109-111 The'n-caprinate oi melting point 55- 57 The palmitate oi melting point 72-- 74 The stearate of melting point 79- 80 The double linkage may be protected by chlorine-tor example, instead of by bromine.

Example 3 I "1.87 Era-1115 9! A S-trans-l'l-cis-androstenedlol-dljacetate of the formula of melting point 168 C. are dissolved in 370cc.

of methanol and the solution is mixed with a solution of 0.28 gram of potassium hydroxide in a small quantity of methanol. The whole is alv lowed to stand at 15 C. for 36 hours, whereupon it is exactly neutralized with dilute hydrochloric acid, and the solution is concentrated in a vacuum to 50 cc. It is then diluted with water and the reaction product is taken up in ether and the ethereal solution is dried and evaporated. By fractionally crystalllzing the residue from hexane, the 17-mono-acetate of A-'*--3-trans-17-cisandrostene-dioi is obtained. This is dissolved in 30 cc.of glacial acetic acid and treated with the calculated quantity (1 mol) of bromine in glacial acetic acid. The bromine is immediately decolorized. There is then added a solution of 1 mol of chromlc acid in acetic acid oi per cent. strength and the whole is allowed to stand overnight at room temperature. The reaction product is then precipitated by addition of water,

filtered, debrominated by shaking in an alcoholic solution-tor 48 hours with zinc dust and. flnally purified by recrystallization from hexane. From the acetate 01 A -androstene-cis-ol-(l7) -.one-' i (3) of melting point C. there is obtained by saponiflcatlon with methyl alcoholic potash'oi 2 'one acetate.

per cent. strength the M- -androstene-cis-ol-(l'l) one-(3) of the formula CHI on E

of melting point 220-221 C.

d ii-trans-1'Z-cis-andmstene-diol-diwetate .is 'obtained by acetylation of A--3-trans-1'l-cisandrostene-dlol-3-acetate, which is itself formed together with 3-trans-17-trans-diol-3-acetate by hydrogenation of A -trans--dehydroandroster- Example 4 I 2.31 grams of A --3-trans-l'l-trans-androstenediol-a-acetate-l7-benzoate of the formula OH: H

' o-co-cim .lized from hexane, yielding brilliant needles of melting point 222-223 C. of the A -3-trans-l'ltrans-androstene-diol- 1'7 -benzoate.

This mono-ester is dissolved in 50 cc. of glacial I acetic acid and there is added, while cooling and in drops, the calculated proportion of a solution of bromine in glacial acetic 'acid. Finally, 0.5 gram of chromium trioxide dissolved in cc. of acetic acid of 90 per cent. strength is added in the cold and the whole is allowed to stand overnight at room temperature, during which time theoxidation product in part crystallizes. 'The mass is then poured into water, the precipitated matter filtered and washed with much water. The brominated ketone thusobtained is debrominated -by violent agitation with zinc dust in glacial acetic acid on the boiling water-bath.v

The mass is then filtered, washed and the solution precipitated by means of water. The precipitate is extracted with ether, the ethereal solution shaken with dilute sodium carbonate solution and water and evaporated. It is also possible to debrominate the brominated ketone by heating a dry solution of it in benzene with an alcoholic solution of sodium iodide. In this case the solution is subsequently washed with aqueous sodium sulfite'solution and water and evaporated.

From the crude product made by one or the other of these methods may be obtained, for instance by.recrystallizing it from hexane or by sublimation in a high vacuum or by both methods,

or bymeans of the sparingly soluble semicarbazone, the A --androstene-trans-ol- 17) -one- (3) benzoate of melting point 193-194" C. By saponiilcation with alcoholic potash this benzoate may The mixture is stirred be converted into the free oxyketone, namely n -androstene-trans-ol-(1'!) cne-(3) of the formula on on. 1!

Example 5 Into 1 liter of ethyl alcohol which has been preheated to C. there are introduced first 5 grams of A -androstene-3,17-diol-3-acetate-17- benzoate of the formula cnrooo of melting point 178-180 C. and then one molecular. proportion of an ethyl alcoholic potash solution (containing 0.64 gram of potassium hydroxide) and the whole is thoroughly stirred for 4 hours at the aforesaid temperature. The solution is neutralized (the'quantity of alkali con- 'sumed amounting to about 10 per cent.) and then highly concentrated in a vacuum and the crude product is shaken with water and ether,

the ethereal solution is separated and evaporated.

By crystallizing the residue from isopropyl ether A -androstene-Zi,ll-diol-l'l-benzoate is obtained in the form of brilliant needles of melting point 222-223 C.

This mono-ester is oxidized with chromic acid. after bromination in glacial acetic acid, in a manner analogous to that described in Example 2. For debrominating the brominated ketone thus obtained the ketone is dissolved in benzene, the solution is carefully dried and then boiled for 3 hours in a reflux apparatus together with a solution of sodium iodide in absolute alcohol. The reaction. mixture is poured into a sodium sulflte solution of .2 per cent. strength, the benzene layer which separates is removed, shaken further with a sodium sulflte solution and with "a'bicarbonate solution and then evaporated. It

Bid

crude A stene-B-one-l'l-ol-benzoate o! EM =52. w. 111% thus may be in 1' pie d. g V

In comparison th the of a methyl alcohoiic potash solution the or an ethyl alcooi melting; point 223 C. are heated in 100 cc. of acetic acid or per cent. strength for 8 hours on the water-hath, and then allowed to stand overnight at room temperature. The reaction puct is precipitated with water, pressed and dried in a vacuum over phosphoms pentoxide. my systematically treating it with benzine (boile ins range 1M0" C.) it is separated into sparii soluble and more easily soluble fractions. The sparingly soluble iraction is unchanged diol. Eyrecrystalliaaton of the more easily soluble fraction from vi alcohol there is abtained the ithmono acetate oi? andrcstane-diol-(3,l7) sch melts at 192 C. This ester is oxidized in the manner described in Example 1, and it rered the oxidation product is saponifled to yield androe-ol-(i7)-one-(3) of the formula CH: cm H of citing point 182 C.

Example 7 d9 grams oi A--androstene-diol-(3,17) of the formula on CH: H

of melting point 182-183 C. and 0.8 gram of acetyl chloride are brought to reaction in pyridine. The reaction mixture is pouredinto water, the pyridine is neutralized by addition of an acid, the precipitated crude product is extracted with pyi, butyl and amyl ether and the ethereal solution is washed" and evaporated. Fractional crystallization of the residue from hexane yields pure A -l'l-acetoxyandrostene-ol-(li) oi melting point 146-148 C. The mono-ester so obtained is brominated; om-

dized with chromic acid in glacial acetic acid and debroniinated with zinc dust and acetic acid in the manner described in Example 2, whereby there is obtainedthe keto-ester, namely A androstene-ol -(ll) -one-(3)-acetate of melting point 141 n. which if required can be converted by saponiflcatlon into the A -androstene-ol- (i'D-one-(il) of the formula CH: CH, H

01' melting point 155 C.

In an analogous manner by partial benzoylation instead 01' acetylation d -androstene-diol-(3,17) can be converted by way of its l'i-mono-benzoate of melting point 222-223 C. into the A -androstene-ol- (17) -one- (3) benzoateof melting point 194-195" C.:.ii' required the latter can be converted by saponification into the above described M -androstene-ol-(ll)-one-(3) of melting point 155 C.

Example 8 2 grams of A -andrQstene-B,i7-diol-17-benzoate oi the formula CH: CH:

n ULO-CO-CJI:

oi melting point 222-223" (3., obtainable as an intermediate product in the process oi Examples 4, and 7, and 2 grams of copper powder are heated at 225 C. in a. vacuum until evolution of gas has ceased. The mass is then treated with 20 cc. oi alcohol, the solution filtered, the solid matter washed and the filtrate is poured into 200 cc. of water and extracted with ether. The ethereal solution is Washed with sodium carbonate solution and water and evaporated. From the residue the A -androstene-o1-(17-one-(3)- benzoate of melting point 193-194 C. is isolated,

for example by i e-crystallization from isopropyl ether and/or sublimation in a'high vacuum or by conversion into its sparingly soluble semicarbazone. By saponiflcation with alcoholic alkali solution the benzoate is converted into the free oxy-ketone, namely A androStene-oI-(I'T) -one- (3) of the formula.

OH: H

of melting point 155 C.

Instead of starting from the 17-monobenzoate the A--androstene-3,17 -diol may be used and Example 9 2 grams of ahdrostane-SA'I-diol-l'l-acetate of the formula cm B O-OO-CH:

no of melting point 192 C., obtainable as an intermediate product in the process of Examples 1 and 6, and 2 grams of cinnamic acid as dissolved in 100 cc. of glacial acetic acid and the solution is shaken while warm with a palladium catalyst. when the reaction is at an end the catalyst is filtered and the filtrate is poured into 800 cc. of water and the liquid is extracted with ether. The ethereal solution is washed with water, dried and evaporated in a vacuum. The residue is saponified while warm with alcoholic alkali solution of 2 per cent. strength and the saponification mixture is poured into water and the whole extracted with ether. The ethereal solution is washed repeatedly with sodium carbonate solution and then with water, whereafter it is evaporated in a vacuum. From the residue androstane-ol-(l'l-one-(li) -of the formula m OH; H

of melting point 182 C. is obtained, for example by recrystallization and/or sublimation in a high vacuum, or by conversion into a sparingly soluble derivative, such as the semicarbazone'or dinitrophenylhydrazone derivative.

Instead of a mixture of androstane-diol-l'lacetate and cinnamic' acid there may be used an androstane-3,17-diol-l'l-cinnamic acid ester, in

which the hydroxyl group to be dehyd'rogenated and the hydrogen acceptor are united in the same molecule.

Example 3.08 grams of I'I-methyl-androstane-diol-(SJ'I) of the formula on. OH:

tic soda solution and water and dried over anhydrous sodium sulfate. From the strongly concentrated ethereal solution the 17-methyl-androstane-ol-(17)-one-(3) of the formula crystallizes. By recrystallization from dilute alcohol it is purified and then melts at 192 C. The

semicarbazone obtained in the usual mannermelts, after recrystallization from absolute alcohol, at 235 C. while decomposing.

' In a similar manner from l'l-ethyl-androstanedim-(3,17) of melting point 205 C. there is obtained the l'l-ethyl-androstane-ol-i17) -one-(3) of melting point 126-127" C. and from 3-trans- Example 11 3.04 grams of A -l'l-methyl-androstene-diol- (3.17) of the formula CH: OH:

a -no of melting point 202-204 C. are dissolved in 50 cc. of glacial acetic acid and mixed with a so1ution'of 1.6 grams of bromine in 10 cc. of glacial acetic acid. To this solution there is added, by drops, one of 0.8 gram of chromium trioxide in cc. of glacial acetic acid. After several hours standing at room temperature the whole is poured into water, the precipitated dibromide is filtered, washed and treated in glacial acetic acid solution with 3 grams of zinc dust. The filtered solution is then poured into water and the precipitated A -l'l-methyl-androstene-ol-(1'1)-one-(8) of the formula OH: Om

is dissolved in ether. The washed and dried ethereal solution is evaporated and the residue recrystallized from dilute alcohol. Its melting point lies'at 161-162 C.

Instead of glacial acetic acid, benzene for example may be used as solvent for the debromination.

In a similar manner A- -androstene-ol-(17)- one- (3) of melting point 155 C. can be obtained from 'A'--androstene-diol-(3.17) of melting point 1812-183 C.

One may also start from compounds which are acylated in l'l-position or substituted in another manner.

matte 12 2.88' moms of ondostene-dione-GJ'Z) of the CH: CH:

of melting point 13%" C. are dissolved in 30 cc. of methyl alcohol ii into this solution there is emdueily introduced. at boiling temperature, the calculated quantity oi sodium. When reduction is complete the precipitate is produced by meeting the mess into water; this is then filtered, Washed with much water and dried over phosphoms pentoxitie. This product is a mixture of ieomeizio emiiosteize ol-onee. The androstene-oll8)-one-=(itioi the formula,

CHa H time he stem-mated from it with the aid of digitomin @ll toy Woy oi" the eemicerloazone and; re ctgretoitiiietl item hexane ill dilute alcohol for iiiiiilottion,

Chin

Emm zle 13 Emit meme oi A -endrostenedione-(3,17) of toemuiei v of melting point FIB-Ne" C. are dissolved in alcohol and hydrogenated with the aid, of a nickel catalyst. When the amount cit hydrogen calculeted for one molecule has been'absorbed. hydroof meiting point 155 43.

met we cieim iez- 1. Process for the manufacture oioxyhetones of the Liil,tl3-oiimethyl cyclopentenopolyhyclmphenenthrene series, consisting in reducing the l'i-izeto group of e i,it-=ethyi-cyclopentenopolyhmroohenenthi'enwalt-dime to the oerhii ioi group.

t. Pi'oeees for the memtiectme of 35 stoneoi=(li) one itl), consisting in reducing the 17-heto group oi emleostene-eiione-(tifi to the oerlooi group.

3. Process for the meimfeoture oi M' -androetene=ol-(i?)-one-(3) consisting in reducing the li heto group oi zi -enoii'oetene-dione(3,17) to the ceihinol group. 

